Breast cancer cutaneous lesions can present either as a local chest wall recurrence or as a site of metastatic disease and will occur in up to 30% of breast cancer patients. Salvage chemotherapy results in overall response rates of 20-30%, at best. Thus, the treatment of cutaneous lesions whether locoregional, i.e. chest wall, or a distant metastasis remains a challenge, and further investigation of novel local treatment strategies are warranted. Imiquimod, a small molecule immune response modifier, generates an immune signal similar to that of pathogenic bacteria, triggering immune activation via toll-like receptor ligand (TLR)-7. Imiquimod has clinical activity against a variety of cutaneous malignancies. Pre-clinical data from our group has shown imiquimod to augment immunity to tumor antigens in an animal model of breast cancer and induce significant tumor regression. Conventional chemotherapy, such as paclitaxel, a commonly used agent in metastatic breast cancer, may also modulate immune function. Immunostimulatory effects of paclitaxel include stimulation of IL-12 production and enhanced NK/LAK cell activity. Abraxane, a new taxane formulation, can be used in conjunction with imiquimod without compromising anti-tumor immunity as it can be administered without the immunosuppressive steroid pre-treatment required with paclitaxel. We hypothesize chemoimmunotherapy with imiquimod and abraxane can lead to higher response rates in breast cancer patients with chest wall or cutaneous metastasis than chemotherapy alone. The specific aims of this proposal are to: (1) determine the safety and therapeutic efficacy of chemoimmunotherapy with topical imiquimod and Abraxane for the treatment of breast cancer patients with recurrent chest wall disease or cutaneous metastasis, (2) examine whether treatment with chemoimmunotherapy consisting of topical imiquimod and Abraxane augments endogenous tumor specific immunity, and (3) assess whether chemoimmunotherapy induces molecular alterations in the tumor microenvironment that have been associated with tumor destructive adaptive immunity. PUBLIC HEALTH RELEVANCE: Breast cancer that has recurred in the chest wall or metastasized in the skin is very difficult to treat and does not respond readily to standard therapy. We propose to treat patients who have chest wall or cutaneous breast cancer with chemoimmunotherapy. Imiquimod is a drug considered to be a biologic agent that profoundly stimulates a local immune response when applied to the skin. Abraxane is a commonly used chemotherapy in the treatment of metastatic breast cancer and can also stimulate the immune system. We will test whether the combination of imiquimod and abraxane is safe and effective in treating chest wall and cutaneous breast cancer metastasis. Moreover, we will study whether the combination boosts immunity directed against the patients tumor;both at the local and systemic level.